The principal aim of the work proposed in this application is to determine where and how the activation fronts arise that initiate ventricular fibrillation, whether from the endocardium, lateral border zone, or epicardium and whether by one or more reentrant pathways or ectopic foci. This will be done by recording simultaneously from 124 electrodes distributed throughout the walls of the left and right ventricles in animal models of conditions thought to occur in individuals with sudden death and coronary artery disease. These conditions include acute ischemia, acute ischemia followed by reperfusion, and old infarction. The hypotheses will be tested that activation can be moderately organized for the first few minutes of fibrillation. If this hypothesis is true, methods to defibrillate the heart will be tested that take advantage of this organization. Epicardial activation during ventricular fibrillation will also be recorded in patients who undergo surgery for life-threatening ventricular tachycardia that is refractory to drugs. Three-dimensional computer displays will be developed to show the spread of activation, possibly interspersed with changing regions of block, during ventricular fibrillation. After determining the mechanism and location of origin of ventricular fibrillation, information will be obtained to help determine why fibrillation arises where and how it does. This will be done by recording the three dimensional distribution of ST segment potentials, T wave potentials, extracellular potassium concentration and extracellular pH and tracking how these variables change with time when ventricular fibrillation begans. The basic understanding of fundamental mechanisms of ventricular fibrillation gained from this work should aid in the development of rational therapy to prevent this most fearsome of all arrhythmias.